There is growing consensus that improved treatment outcomes for substance use disorders may be achieved through integration of psychosocial and pharmacologic interventions. The present proposal will assess the ability of the b-blocker propranolol to disrupt cocaine cue-induced craving and reactivity. Supporting rationale for the proposed study comes from both preclinical studies showing that b-blocking agents can disrupt memory reconsolidation processes underlying fear-based associative learning and from clinical studies suggesting that combining b-blocking agents with exposure-based therapy may reduce PTSD symptoms. Important support for the proposed research also comes from recent preclinical studies indicating that b-blocking agents may alter memory reconsolidation processes involved in appetitive drug-related conditioning. As these intriguing findings have yet to be extended to a human proof-of-concept study with potential clinical applications, the proposed study represents the first translational human laboratory research effort to evaluate the effects of propranolol administration on the putative memory processes elicited by cocaine cue exposure. The specific aim of this proposal is to examine the effects of propranolol vs. placebo, administered immediately after a retrieval session of cocaine cue exposure, on craving and physiological responses occurring during a subsequent test session of cocaine cue exposure. We hypothesize that, compared to cocaine-dependent (CD) individuals treated with placebo, propranolol-treated CD individuals will evidence less craving and physiological arousal during the test session. We also expect that any between-group differences identified during the test session will be maintained at 1-week follow-up. Fifty-two CD men and women will be randomly assigned to receive an acute dose of either 40 mg immediate-release propranolol or placebo immediately after the first of two cocaine-cue exposure sessions scheduled on consecutive days. Participants will remain in the Medical University of South Carolina's General Clinical Research Center (GCRC) throughout the two-day testing period to prevent drug use. Medications will be administered in a double-blind fashion. All participants will return one-week after their GCRC inpatient stay to undergo a follow-up cue exposure session. Craving and physiological reactivity will be measured prior to, during, and following all cue exposure sessions. Encouraging findings from this study could lead to a controlled treatment trial in which strategic propranolol administration would serve as an element of a multi-component cue exposure intervention. Conceivably, propranolol could become one of several novel and effective pharmacotherapy adjuncts that augment the treatment outcomes achieved with existing exposure-based interventions for drug abuse (e.g., methamphetamine, marijuana and opiates). Consistent with NIDA's mission, the long-term goal of this project is to improve substance use disorders treatment through the identification of innovative and novel approaches to treatment development/refinement. PUBLIC HEALTH RELEVANCE: This innovative translational research endeavor will employ an established cue reactivity/exposure methodology to assess the therapeutic potential of an untested and potentially promising adjunctive pharmacotherapy for one of the most intractable substance use disorders, cocaine dependence. It is hoped the results of this proof-of-concept investigation will lead to the development of a pharmacotherapeutic treatment element that will enhance the outcomes of exposure-based treatment for cocaine dependence and be generalizable to addiction problems involving other substances of abuse.